Potassium depletion selectively inhibits sustained diacylglycerol formation from phosphatidylinositol in angiotensin II-stimulated, cultured vascular smooth muscle cells

Potassium depletion decreases blood pressure in vivo and blunts the pressor response to angiotensin II (ang II) without down-regulating the receptor. In cultured rat aortic smooth muscle cells, the ang II-induced signaling sequence is biphasic with rapid hydrolysis of the polyphosphoinositides producing an early (15 s) diacylglycerol (DG) peak and a transient rise in inositol trisphosphate (IP3) and more delayed phosphatidylinositol (PI) hydrolysis resulting in sustained DG formation (peak at 5 min). Exposure of intact vascular smooth muscle cells to low potassium growth medium for 24 h or acutely potassium-depleting cells with nigericin causes selective, marked inhibition of late DG formation (5-min peak inhibited by 60 +/- 8% and 84 +/- 7%, respectively). The early cell response, namely polyphosphoinositide hydrolysis, inositol bis- and trisphosphate production and the 15-s DG peak, is not affected. Analysis of 125I-ang II-binding data reveals no significant differences in either receptor number or binding affinity (Kd) in potassium-depleted cells. Together with its marked inhibitory effect on sustained ang II-induced DG formation, acute potassium depletion effectively blocks internalization of 125I-ang II: there is no significant internalization of the ligand after 5 min at 37 degrees C versus 64 +/- 7% internalization in control cells. Thus, potassium depletion does not alter ang II binding or initial membrane signaling in rat aortic smooth muscle but blocks ligand internalization and selectively and markedly inhibits the development of direct PI hydrolysis and sustained diacylglycerol formation. These findings suggest a role for ligand-receptor processing in generating the sustained cell response and potentially explain the lower blood pressure and decreased pressor response to ang II seen in hypokalemic states in vivo. Furthermore, the ability of K+ depletion to alter secondary signal generation may provide insight into the mechanisms underlying the K+ dependence of a variety of cell functions.     

Nutritional ecology and diachronic trends in Paleolithic diet and health

Modern nutritional studies have found that diverse diets are linked to lower infant mortality rates and longer life expectancies in humans. This is primarily because humans require more than fifty essential nutrients for growth and cell maintenance and repair; most of these essential nutrients must come from outside food sources rather than being manufactured by the body itself; and a diversity of food types is required to consume the full suite of essential nutrients necessary for optimal human health. These principles and their related affects on human adaptations and demography are the hallmarks of a theoretical paradigm defined as nutritional ecology. This essay applies concepts derived from nutritional ecology to the study of human evolution. Principles of nutritional ecology are applied to the study of the Middle‐to‐Upper Paleolithic transition in order to broadly illustrate the interpretive ramifications of this approach. At any stage in human evolution, those hominid populations that chose to diversify their subsistence base may have had a selective advantage over competitors who restricted their diet principally to one food type, such as terrestrial mammals.     

Nitroimidazole conjugates of bis(thiosemicarbazonato)Cu(II) - Potential combination agents for the PET imaging of hypoxia

Combination agents comprising two different pharmacophores with the same biological target have the potential to show additive or synergistic activity. Bis(thiosemicarbazonato)copper(II) complexes (e.g. ⁶⁴Cu-ATSM) and nitroimidazoles (e.g. ¹⁸F-MISO) are classes of tracer used for the delineation of tumor hypoxia by positron emission tomography (PET). Three nitroimidazole-bis(thiosemicarbazonato)copper(II) conjugates were produced in order to investigate their potential as combination hypoxia imaging agents. Two were derived from the known bifunctional bis(thiosemicarbazone) H₂ATSM/A and the third from the new precursor diacetyl-2-(4-N-methyl-3-thiosemicarbazone)-3-(4-N-ethylamino-3-thiosemicarbazone) - H₂ATSM/en. Oxygen-dependent uptake studies were performed using the ⁶⁴Cu radiolabelled complexes in EMT6 carcinoma cells. All the complexes displayed appreciable hypoxia selectivity, with the nitroimidazole conjugates displaying greater selectivity than a simple propyl derivative used as a control. Participation of the nitroimidazole group in the trapping mechanism is indicated by the increased hypoxic uptake of the 2- vs. the 4-substituted ⁶⁴Cu-ATSM/A derivatives. The 2-nitroimidazole derivative of ⁶⁴Cu-ATSM/en demonstrated superior hypoxia selectivity to ⁶⁴Cu-ATSM over the range of oxygen concentrations tested. Biodistribution of the radiolabelled 2-nitroimidazole conjugates was carried out in EMT6 tumor-bearing mice. The complexes showed significantly different uptake trends in comparison to each other and previously studied Cu-ATSM derivatives. Uptake of the Cu-ATSM/en conjugate in non-target organs was considerably lower than for derivatives based on Cu-ATSM/A.